THU0048 1, 25(OH)2D3 Inhibits Th17 Polarization and RORC Expression Through GATA3-Dependent and -Independent Mechanisms. (23rd January 2014)

• Record Type: Journal Article
• Authors: Dankers, W.; van Hamburg, J. P.; Mus, A.-M. M.; Asmawidjaja, P. S.; van Leeuwen, J. P.; Hendriks, R. W.; Boon, L.; Colin, E. M.; Lubberts, E.
• Is Part Of: Annals of the rheumatic diseases. Volume 72:Supplement 3(2013)
• Page Start: A180
• Page End: A180
• Publication Date: 2014-01-23
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2013-eular.576
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Vitamin D has suppressive effects on autoimmune diseases, such as rheumatoid arthritis (RA). Regulation of Th17 cell activity is an important mechanism by which vitamin D exerts these effects. Aside from inhibiting Th17 cytokines and the Th17 transcription factor Rorγt, vitamin D induces IL-4 and GATA3. Interestingly, GATA3 over-expression inhibits experimental Th17-mediated autoimmunity. Objectives: We studied the contribution of GATA3 in vitamin D-mediated suppression of Th17 polarization. Methods: CD4 + T cells were sorted from patients with early RA, naïve DBA-1 mice, DBA-1 mice immunized with collagen type II (CII) or naïve CD2-GATA3 transgenic mice and cultured under T helper cell polarizing conditions with or without 1, 25(OH)2 D3, the active form of vitamin D. Results: 1, 25(OH)2 D3 inhibits Th17 polarization in CD4+ cells from both non-immunized and CII-immunized mice, while up-regulating IL-4 and GATA3 expression. In these cultures, IL-4 inhibition partly reversed the vitamin D-mediated inhibition of Th17 polarization. Moreover, GATA3 over-expression reduces Th17 differentiation to a lower level than 1, 25(OH)2 D3 . Interestingly, combining GATA3 over-expression and 1, 25(OH)2 D3 treatment reduced IL-17A and Rorγt expression even further. Furthermore, gene-expression analysis showed that NFAT-C2, which is involved in IL-17A production, was down-regulated by 1, 25(OH)2 D3 . In addition, in T cells from patients with RA, 1, 25(OH)2 D3 inhibited Th17 cytokine and RORγt expression and induced IL-4 and GATA3 expression. Conclusions: These data show that vitamin D-mediated regulation of Th17 polarization occurs through GATA3-dependent mechanisms, including direct effects on RORγt expression and IL-4-mediated inhibition of Th17 polarization. Moreover, GATA3-independent mechanisms are involved that may include modulation of NFAT-C2 expression. Disclosure of Interest: None Declared